Engineered bacteria increase intratumoral L-arginine which synergizes with immune checkpoint therapies.
Major Finding: Engineered bacteria increase intratumoral L-arginine which synergizes with immune checkpoint therapies.
Concept: To improve antitumor T-cell response, nonpathogenic bacteria were engineered to convert ammonia to L-arginine.
Impact: Engineered microbial therapies could potentially enhance the efficacy of cancer immunotherapy.
A key component needed for T-cell metabolic and survival fitness to promote efficient antitumor response is L-arginine; however, in tumors the concentration of L-arginine is generally low due to the enhanced metabolism of tumor cells. An increase in intratumoral L-arginine levels could potentially improve the response to immune checkpoint inhibitors, but ingestion of enough L-arginine to produce the desired response is unfeasible, whereas injection of a saturated solution directly into the tumor results in rapid diffusion out of the tumor; therefore, alternative methods are needed. Canale, Basso, and colleagues developed an engineered probiotic using the nonpathogenic Escherichia coli Nissle 1917 (ECN) which colonizes tumors and converts ammonia (which is abundant in tumors) to L-arginine. Intratumoral levels of L-arginine were increased upon the persistent colonization of this bacteria as were the number of infiltrating CD4+ and CD8+ T cells with a concomitant decrease in FOXP3+ T regulatory cells. Use of ECN in combination with an anti–PD-L1 antibody in mouse colon cancer models showed synergistic effects in the ability to clear tumors with complete eradication seen in 74% of combination-treated mice. This effect was further confirmed to be T cell–dependent, and sustained effector T-cell function was shown through an increase in production of the inflammatory cytokine TNF and the reduction in coexpression of the inhibitory receptors PD-1 and LAG3. Furthermore, mice that exhibited complete tumor regression did not produce tumors upon subcutaneous rechallenge with tumor cells, indicating the presence of antitumor memory, and transfer of memory T cells from these mice demonstrated superior antitumor effects in recipient mice. Switching to intravenous injection of these bacteria also led to persistent colonization of tumors over 100 mm3, and, although a reversible reduction in mouse body weight was noted, tumor size was reduced when combined with anti–PD-L1 therapy. This study shows a way to enhance immunotherapy efficacy through use of engineered microbial therapies and suggests further development toward clinical evaluation.
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